PS1 FAD mutants inactivate ephrinB1 and BDNF‐dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of NMDA receptor

Abstract Background Excitotoxicity is thought to play a key role in brain neurodegeneration and stroke. Here, we show that neuroprotection against excitotoxicity by trophic factors ephrinB1 (efnB1) and BDNF (called here Factors) involves de novo formation of “survival complexes” which are Factor‐stimulated complexes of NMDA receptor (NMDAR) with Factor receptor (FR) and PS1. Method Primary cortical neuronal cultures from wild type or from PS1 hemizygous (PS1+/‐) or homozygous (PS1‐/‐) knockout (KO) mouse embryos were used to examine the role of PS1 on NMDAR‐FR complex formation. We also used two independently constructed PS1 FAD mutant knock‐in (KI) mice, one expressing human FAD mutant allele PS1 M146V and the other expressing FAD allele I213T, to test the effects of PS1 FAD mutants on Factors‐dependent neuroprotection, NMDAR complexes with FR and PS1, and NMDAR EPSCs. In addition, postmortem human brains carrying PS1 FAD mutants were used to test the relevance of our study in human disease mechanism. Result Absence of PS1 reduces the formation of survival complexes and abolishes neuroprotection. EphB2‐ and NMDAR‐derived peptides designed to disrupt formation of survival complexes also decrease the Factor‐stimulated neuroprotection. Strikingly, the neuroprotective effect of Factors and the levels of de novo Factor‐stimulated survival complexes decrease dramatically in neurons expressing PS1 Familial Alzheimer disease (FAD) mutants. Mouse neurons and brains expressing PS1 FAD mutants contain increased amounts of constitutive PS1‐NMDAR complexes. Additional evidence indicate that constitutive PS1‐NMDAR complexes formed in PS1 FAD mutant‐expressing neurons may differ from those formed in WT neurons and that neurons of PS1 FAD mutant‐expressing brains are more vulnerable to cerebral ischemia than neurons of WT brains. Furthermore, NMDAR‐mediated EPSCs at CA1 synapses are altered by PS1 FAD mutants. Importantly, high levels of PS1‐NMDAR complexes were also found in postmortem brains of AD patients expressing PS1 FAD mutants. Conclusion Together, our data identify a novel PS1‐dependent neuroprotective mechanism against excitotoxicity and indicate a pathway by which PS1 FAD mutants may decrease Factor‐depended neuroprotection against toxic insults. These findings have implications for the pathogenic effects of FAD mutants and therapeutic strategies.